Structure-Based Optimization of Arylamides as Inhibitors of Soluble Epoxide Hydrolase

Abstract

Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection. The screen identified N-(3,3-diphenyl-propyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.

18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase

“…1), a potent sEH inhibitor (see below) with molecular properties (log P of 2.9 and molecular weight MW of 334 Da) optimal for brain PET radiotracers (22). FNDP is structurally similar to the sEH inhibitor N -(3,3-diphenylpropyl)-nicotinamide (nor-fluoro-FNDP), identified by Boehringer Ingelheim as an sEH inhibitor (human IC 50 of 7 nM) with improved “drug-like” characteristics (18) and was used here as a lead compound for development of FNDP and blocker in animal experiments. In vitro assay demonstrated that FNDP is a sEH inhibitor with higher potency than that of the lead nor-fluoro-FNDP and comparable to the sEH inhibitor AUDA (supplemental data, Supplemental Figure 2).…”

“…Inhibitory activity of FNDP and nor-fluoro-FNDP, an analogue of FNDP and known inhibitor of sEH (18), was measured using the sEH Inhibitor Assay Kit (Cayman Chemical, MI). In brief, IC 50 values of the sEH inhibitors were determined by measuring the inhibition of hydrolysis of (3-phenyl-oxiranyl)-acetic acid cyano-(6-methoxy-naphthalen-2-yl)-methyl ester by sEH.…”

“…1), rodent biodistribution and baboon brain PET imaging of N -(3,3-diphenylpropyl)-6- 18 F-fluoronicotinamide ( 18 F-FNDP), a radiotracer for sEH that is structurally similar to the potent sEH inhibitor N -(3,3-diphenylpropyl)-nicotinamide (18) (nor-fluoro-FNDP).…”

Structure–activity relationships of substituted oxyoxalamides as inhibitors of the human soluble epoxide hydrolase

“…Functionalities such as amides and carbamates with both a carbonyl group and an NH group are, therefore, known to produce potent inhibition as a primary pharmacophore, while ester or carbonate functions without a proton donating NH group yield no inhibition for the target enzyme. 12,22–24 Many of these compounds are difficult to formulate because they are high melting liphophilic solids. These formulation problems can be solved by reducing the melting point and crystal stability, increasing water solubility, and increasing potency.…”

Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides

“…6 Over the years, more potent urea-inhibitors that display better solubility and availability as well as significant biological activities in both in vitro and in vivo models were obtained. 7 Interestingly, beside the effort of many groups and the screening of several libraries of small chemicals, 8–12 to date only the Merck group was successful in replacing the urea or amide pharmacophore with a benzisoxazole, which inhibit the sEH in the nanomolar range. 10 Recently, chalcone 13 and benzoxazolone 14 derivatives as well as salvionic acid A 15 were reported to inhibit sEH; however, these compounds are at least a 1,000-fold less potent than the best sEH inhibitors available.…”